der(21)t(1;21)(q11-12;p11-13) and der(21)t(1;21)(q21-32;p11-13)

Abstract

Unbalanced chromosome translocations involving all or part of the whole long arm of chromosome 1 and the short arms of acrocentric chromosomes are widely reported in human neoplasia. Among them, chromosome translocations between the long arm of chromosome 1 and chromosome 21 have been reported in patients with various conditions, including myeloid malignancies, acute lymphoblastic leukemia, multiple myeloma and lymphomas.

Keywords

Gain of 1q; unbalanced translocations; gene overexpression; acrocentric chromosome.

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Identity

ICD-Topo	C420,C421,C424
ICD-Morpho	9950/3 Polycythaemia vera
ICD-Morpho	9945/3 Chronic myelomonocytic leukaemia
ICD-Morpho	9982/3 Refractory anemia with ring sideroblasts associated with marked thrombocytosis; Refractory anaemia with ring sideroblasts
ICD-Morpho	9983/3 Refractory anaemia with excess blasts
ICD-Morpho	9866/3 Acute promyelocytic leukaemia with t(15;17)(q22;q12); PML-RARA
ICD-Morpho	9891/3 Acute monoblastic and monocytic leukaemia
ICD-Morpho	9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho	9837/3 T lymphoblastic leukaemia/lymphoma
ICD-Morpho	9733/3
ICD-Morpho	9687/3 Burkitt lymphoma
ICD-Morpho	9732/3 Plasma cell myeloma / Multiple myeloma
ICD-Morpho	9680/3 Diffuse large B-cell lymphoma (DLBCL), NOS; Primary DLBCL of the CNS; Primary cutaneous DLBCL, leg type; EBV positive DLBCL of the elderly; DLBCL associated with chronic inflammation; B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
ICD-Morpho	9700/3 Mycosis fungoides
Atlas_Id	1478

Clinics and Pathology

Disease	Chronic and acute myeloid malignancies, acute lymphoblastic leukemia (ALL), multiple myeloma (MM) and various lymphoid neoplasms.
Embryonic origin
Epidemiology	There were 13 males and 10 females (1 unknown) aged 8 to 90 years old (median 65 years) in a group of patients with 1q11-12 translocations (Table 1). Patients with 1q25-32 translocations tended to be younger and included 6 males and 5 females aged 0 to 72 years (median age 17 years), 2 of them were infants (Felix et al., 1998; Chessells et al., 2002) (Table 2).   SEX/AGE DISEASE KARYOTYPE MYELOPROLIFERATIVE DISORDERS  1 M/68 CMML 46,XY,der(21)t(1;21)(q11;p11) 2 F/76 PV 46,XX,der(4)t(1;4)(q12;p16)/46,XX,der(21)t(1;21)(q12;p12) 3 F ET 46,XX,der(21)t(1;21)(q11;p13) MYELODYSPLASTIC SYNDROME 4 M/56 MDS APL-like 47,XY,+11 47,XY,t(4;11)(q10;p15),+11/48,idem,+8/48,idem,+11/48,idem,+13/48,idem,+17/48,idem,+19/47,idem,der(22)t(1;22)(q12;p13) 47,XY,t(4;11),+11,der(21)t(1;21)(q12;p13)  5 F/75 RARS 46,XX,del(20)(q11)/46,idem,der(21)t(1;21)(q12;p11) 6 F/80 RAEB 46,XX,der(21)t(1;21)(q10;p10) ACUTE MYELOID LEUKEMIA 7 M/36 AML 58,XY,-X,-1,-3,-4,-5,+6,-7,-9,-10,-12,der(15)t(1;15)(q12;p11),-16,-17,-18,-21/58,idem,-der(15),der(21)t(1;21)(q12;p11)/47,XY,+8 ACUTE LYMHOBLASTIC LEUKEMIA 8 M B-ALL 46,XY,der(19)t(1;19)(q23;p13)/46,idem,der(21)t(1;21)(q12;p13) 9 F ALL 46,XX,der(19)t(1;19)(q23;p13)/46,idem,der(21)t(1;21)(q11;p11) 10 M ALL 46,XY,del(13)(q1?2),der(21)t(1;21)(q12;p12) 11   B-ALL 46,X?,der(1)t(1;19)(q23;p13),i(7)(q10),der(21)t(1;21)(q12;p13) 12 M B-ALL 46,XY,del(6)(q13q23),der(19)t(1;19)(q23;p13)/46,idem,der(21)t(1;21)(q12;p11) MULTIPLE MYELOMA 13 M MM 43,X,-Y,+1,der(1;15)(q10;q10),der(4)t(1;4)(q11;q35),-13,-14,der(21)t(1;21)(q11;p11),-22  /td> 14 F MM 44,X,-X,der(6)add(6)(p25)t(1;6)(q12;q12),?inv(7)(p14p22),del(8)(p11),-13,del(20)(q12),der(21)t(1;21)(q10;p11) 15 F MM 44-45,XX,del(1)(p13p32),t(2;14)(p23;q32),t(4;14)(p16;q32),add(5)(q33),der(5)t(1;5)(q10;p15),der(7;7) t(7;7)(p22;?q33)add(7)(p22),-13,del(14)(q24),der(21)t(19;21)(?p13;p11),add(21)(p11)/45,XX,der(1) del(1)add(1)(q32),t(2;14),t(4;14)(p16;q32),add(5),der(5)t(1;5)(q11-12;p15),-13,del(14),der(19)t(1;19)  (q11-12;q13),der(21)t(19;21),add(21)/45,XX,der(1)del(1)add(1),t(2;14),t(4;14)(p16;q32),add(5),der(5)t(1;5),-13,del(14),der(14)del(14)t(1;14)(q11-12;q24),der(21)t(19;21),add(21)/45,XX,der(1)del(1)add(1), t(2;14),t(4;14)(p16;q32),add(5),der(5)t(1;5),-13,del(14),der(21)t(1;21)(q11-12;p11),der(21)t(19;21), add(21) 16 F MM 46,X,-X,add(1)(q21),ider(1)(q10)del(1)(q42),?del(5)(p15),+hsr(7)(p15),der(8)t(1;8)(p13;q24),+add(9) (p12),der(10)t(1;10)(q21;p13)add(10)(q26),del(11)(q21q23),del(13)(q12q22),i(13)(q10),-14,add(15)(q26),der(18)t(1;18)(q12;q23),add(20)(q13),der(21)t(1;21)(q12;p13)ins(21;?)(p13;?),add(22)(p11) NON HODGKIN LYMHOMA 17 M/8 MBN 46,XY,der(8)t(7;8)(q21;q24)dup(7)(q21q36),der(14)t(8;14)(q24;q32),der(21)t(1;21)(q11;p13) 18 M MBN 42-47,XY,add(3)(q11),add(8)(q24),der(14)t(8;14)(q24;q32),t(14;18)(q32;q21),del(16)(q13),+20/42-47, idem,der(21)t(1;21)(q11;p11)/47-48,idem,+X/47-48, idem,+7/49,idem,+X,+7 LN 19 F FL 49-50,X,del(X)(p21),dic(1;12)(?p21;q24),t(3;4)(q27;p13),+i(6)(p10),t(14;18)(q32;q21),i(17)(q10), +add(19)(q13),der(21)t(1;21)(q11;p11),+2mar LN 20 F FL 42-54,XX,t(6;7)(p21;q22),+7,+der(7)t(6;7),t(8;14)(q24;q32),+11,+11,+12,+der(14)t(8;14),+21,der(21)t(1;21)(q12;p13)x2 LN 21 M DLBCL 46,X,-Y,add(1)(p32),dup(1)(q21q31),t(3;14)(q27;q32),add(8)(p11),del(9)(p11),der(21)t(1;21)(q12;p13), +mar LN LN 22 M/90 BL 46,XY,t(8;14)(q24;32),der(21)t(1;21)(q14;p12) LN OTHERS 23 M/65 PCL 82-87,XXY,-Y,-1,-2,-3,-4,-5,del(6)(q21)x2,-8,del(8)(p21),-10,-10,add(11)(p15)x2,-13,-13,-14,-15,-15,-18, +19,der(20)t(1;20)(q11;q13)ins(20;?)(q13;?)x2,der(21)t(1;21)(q11;p13)ins(21;?)(p13;?),-22,inc 24 M/30 HD 46,X,-Y,del(4)(q28),+8,add(9)(p24),der(14)t(1;14)(q11;p11),der(21)t(1;21)(q11;p11) LN Abbreviations: M, male; F, female; CMML, Chronic myelomonocytic leukemia; PV, Polycythemia vera; ET,  Essential thrombocythemia; MDS, Myelodysplastic syndrome; APL, Acute promyelocytic leukemia; RARS, Refractory anemia with ringed sideroblasts;  RAEB, Refractory anemia with excess of blasts; AML, Acute myeloid leukemia; ALL, Acute lymphoblastic leukemia/lymphoblastic lymphoma;  MM, Multiple myeloma; MBN, Mature B-cell neoplasm; LN, lymph node; FL, Follicular lymphoma; DLBCL, Diffuse large B-cell lymphoma; BL, Burkitt lymphoma/leukemia; PCL, Plasma cell leukemia; HD, Hodgkin disease. 1. Amenomori et al., 1986; 2. Juneau et al., 1998; 3. Gangat et al., 2009; 4. Najfeld et al., 1994; 5. Huh et al., 2010; 6. Makishima et al., 2013; 7. Liu et al., 2007; 8. Raimondi et al., 1990; 9. Uckun et al., 1998; 10. Heerema et al., 2000; 11. Lu et al., 2002; 12. Bousquet et al., 2007; 13. Sawyer et al., 1998; 14. Sawyer et al., 1998; 15. Gabrea et al., 2008; 16. Sawyer et al., 2014; 17. Dayton et al., 1994; 18. Schmitz et al., 1997; 19. Roumier et al., 2000; 20. Katzenberger et al., 2004; 21. Ruminy et al., 2006; 22. Trcic et al., 2010; 23. Andreasson et al., 1998; 24. Stamatoullas et al., 2007   SEX/AGE DISEASE KARYOTYPE ACUTE MYELOID LEUKEMIA 1 M/0 AML-M5 46,XY,der(1)t(1;1)(p36;q21)/45,idem,-Y/47,idem,+8/46,XY,der(21)t(1;21)(q21;p11) B-CELL ACUTE LYMHOBLASTIC LEUKEMIA 2 M ALL 46,XY,der(21)t(1;21)(q21;p13)dup(1)(q21q32) 3 F/0 ALL 47,XX,+X,t(11;19)(q23;p13),der(21)t(1;21)(q25;p11) 4 M/11 ALL 46,XY,del(6)(q13q21),der(19)t(1;19)(q23;p13),der(21)t(1;21)(q21;p11) 5 M/50 ALL 46,XY,der(8)t(8;9)(p22;p24)t(8;22)(q24;q11),der(9)t(8;9)(p21;p24),der(21)t(1;21)(q21;p11),der(22)t(8;22) (q24;q11) 46,XY,t(8;9)(q22;q24) 46,XY,der(8),der(9)x2,der(21),der(22)/46,idem,der(16)t(16;22)(q24;q11)  T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA 6 M/72 ALL 46,XY,der(21)t(1;21)(q25;p11)  MULTIPLE MYELOMA 7 F MM 39-41,-X,der(X)t(X;18)(q28;q11)ins(X;?)(q28;?),t(1;8)(p11-13;q24),add(2)(p25),dup(3)(q21q29), add(4)(q?31),t(4;14)(p16;q32),add(7)(p22),-8,der(9;17)(p10;q10),der(10)t(8;10)(q11;p13),-13,-14, add(15)(p11),der(15)t(9;15)(q12;p11),der(18)t(X;18),add(19)(q13),+20, der(21)t(1;21)(q23;p11) ins(21;?)(p11;?),+mar 8 F MM 39-45,XX,der(1;21)(p10;q10),+r(?1)(p13q?31),der(2)t(1;2)(q12;q37),add(3)(q29),der(4;18)(p10;q10), add(5)(q34),+7,add(10)(q26),add(12)(p12),-13,add(15)(p11),der(15)t(?14;15)(q31;q24),add(17)(q25), der(19)t(?7;19)(p13;q13),add(20)(p12),der(21)t(1;21)(q?31;p13) NON HODGKIN LYMHOMA 9 F/17 BL 46,XX,del(7)(q22q32),t(8;14)(q24;q32)/46,idem,t(1;18)(q11;p11)/46,idem,t(1;21)(q11;p11) 48,X,der(X)t(X;8)(q11;q11),+del(3)(q21q29),t(3;16)(p12;q24),+del(7),t(8;14),?del(14)(q11q21), der(21)t(1;21)(q21;p13) 10 F/67 DLBCL 51-56,XX,+X,+del(1)(q21),+2,+5,+6,+7,+del(8)(q24),+9,+10,+11,+13,+14,+17,+20,-21,der(21 t(1;21)(q21;p11),-22,-22,+2mar exudate OTHERS 11 M/65 MF/SS 45,XY,der(1)t(1;17)(p13;q21),t(2;5)(p14;q14),t(3;7)(p21;q35),t(4;9)(p?15;p?22),-5,-6,-9,-11,del(12)(q22),-17,-19,add(19)(q13),der(21)t(1;21)(q32;p13),+5mar Abbreviations: M, male, f, female, BL, AML-M5, Acute monoblastic leukemia; ALL, Acute lymphoblastic leukemia; MM, Multiple myeloma; Burkitt lymphoma/leukemia; DLBCL, Diffuse large cell lymphoma; MF/SS, Mycosis fungoides/Sezary syndrome. 1. Chessells et al., 2002; 2. Raimondi et al., 1990; 3. Felix et al., 1998; 4. Andersen et al., 2011; 5. Patterer et al., 2013; 6. Safavi et al., 2015; 7. Gabrea et al., 2008; 8. Sawyer et al., 2014; 9. Fitzgerald et al., 1984; 10. Gladstone et al., 1994; 11. Schlegelberger et al., 1994. Patients with centromeric 1q11-12 translocations were diagnosed mainly with myeloid malignancies and lymphomas Myeloid malignancies in 7: 1 chronic myelomonocytic leukemia (CMML) (Amenomori et al., 1986), 1 myelodysplastic syndrome (MDS)/ acute promyelocytic leukemia (APL)-like leukemia (Najfeld et al 1994), 1 polycythemia vera (PV) (Juneau et al., 1998), 1 essential thrombocythemia (ET) (Gangat et al., 2009), 1 refractory anemia with ringed sideroblasts (RARS) (Huh et al., 2010), 1 refractory anemia with excess of blasts (RAEB) (Makishima et al., 2013) and 1 acute myeloid leukemia (AML) (Liu et al., 2007). Acute lymphoblastic leukemia in 5 (Raimondi et al., 1990; Uckun et al., 1998; Heerema et al., 2000; Lu et al., 2002; Bousquet et al., 2007). Multiple myeloma in 4 (Sawyer et al., 1998; Gabrea et al., 2008; Sawyer et al., 2014). Various lymphoid malignancies in 7: 2 mature B-cell neoplasm (MBN) (Schmitz et al., 1997; Dayton et al., 1994), 1 Burkitt lymphoma/leukemia (BL) (Trcic et al., 2010), 1 Plasma cell leukemia (PCL) (Andreasson et al., 1998), 2 follicular lymphoma (FL) (Roumier et al., 2000; Katzenberger et al., 2004), 1 diffuse large B-cell lymphoma (DLBCL) (Ruminy et al., 2006) and 1 HD (Hodgkin disease) (Stam atoullas et al., 2007). der(21)t(1;21) with 1q21-32 breakpoints was less frequent and has been detected mainly in patients with ALL: 4 of them were diagnosed with B-cell ALL (Raimondi et al 1990; Felix et al., 1998; Andersen et al., 2011; Patterer et al., 2013) and 1 patient with T-ALL (Safavi et al., 2015). In addition, there were sporadic cases with other malignancies: 1 acute monoblastic leukemia (AML-M5) (Chessells et al., 2002), 1 diffuse large B-cell lymphoma (DLBCL), 1 Burkitt lymphoma/leukemia (BL) (Fitzgerald et al., 1984), 1 mycosis fungoides/Sezary syndrome (MF/SS) (Schlegelberger et al., 1994) and 2 multiple myeloma patients (Gabrea et al., 2008; Sawyer et al., 2014).
Prognosis	Associated with poor-risk genetic features and/or complex karyotypes in the majority of described patients, indicative of chromosomal instability related to disease progression and therapy resistance.

Cytogenetics

Cytogenetics Morphological	der(21)t(1;21)(q11-12;p11-13) has been detected as sole anomaly in 3 myeloproliferative disorders (Amenomori et al., 1986; Gangat et al., 2009; Makishima et al., 2013), found in association with trisomy 11 in MDS transforming to APL-like leukemia (Najfeld et al., 1994), del(20)(q11) in RARS (Huh et al., 2010) and additional 1q abnormalities in PV (Juneau et al., 1998) and AML patients (Liu et al., 2007). In patients diagnosed with ALL, there was a notable association with der(19)t(1;19)(q23;p13) as except 1 case with del(13q), in the remaining 4 ALL patients der(19)t(1;19)(q23;p13) was detected. Associated with t(8;14)(q24;q32) in 4 mature B-cell/Burkitt lymphoma/leukemia (Dayton et al., 1994; Schmitz et al., 1997; Katzenberger et al 2004; Trcic et al 2010) and with highly complex karyotypes in the remaining patients. In the group of patients with 1q21-32 breakpoints , sole anomaly was detected only in 1 T-ALL (Safavi et al., 2015); found in association with t(11;19)(q23;p13) in an infant with B-ALL (Felix et al., 1998), der(19)t(1;19)(q23;p13) in the pediatric B-ALL (Andersen et al., 2011), t(8;22)(q24;q11) in 1 B-ALL (Patterer et al., 2013) and (8;14)(q24;q32) in the BL patient (Fitzgerald et al., 1984). Found in the sideline with der(1)t(1;1)(p36;q21) and -Y/ +8 in infant with AML-M5 (Chessells et al., 2002) and as a part of complex karyotypes in the remaining patients.
	Figure 1. Partial karyotypes with der(21)t(1;21)(q11-12;p11-13) (A). Fluoresce in situ hybridization with LSI RUNX1/ RUNX1T1 probe (Vysis/Abott Molecular, US) revealing hybridization of RUNX1 probe to der(21) chromosome (green signal). (B). Hybridization with LSI 1p36/1q25 probe on metaphases and interphase cells showing the presence of extra green signal of 1q25 on der(21) chromosome and in interphase cells (green signal) (C).
	Figure 2. Partial karyotypes with der(21)t(1;21)(q21;p11-13) (A). Fluorescence in situ hybridization with LSI 1p36/1q25 probe (Vysis/Abott Molecular, US) on metaphase showing the extra 1q25 signal on der(21) chromosome and in interphase cells (B).

Result of the chromosomal anomaly

Fusion Protein

Oncogenesis

Unbalanced 1q translocations to the short arms of acrocentric chromosomes are recurrent chromosome anomalies detectable in both hematologic neoplasms and lymphomas. Their main consequence is an extra copy of part of the long arm of chromosome 1 resulting in gene dosage abnormalities. Unbalanced translocations involving 1q and an acrocentric chromosome typically do not involve key genes, but they have as main consequence gain of the long arm of chromosome 1. 1q gains typically involve large chromosome regions, therefore simultaneous overexpression of multiple genes that might cooperate in an additive or synergistic way is likely implicated in neoplastic processes. der(21)t(1;21) was apparently a late event in the majority of reported patients- occurring together with the well-known primary abnormalities or as part of complex karyotypes, therefore representing clonal evolution change preceding or accompanying disease evolution.

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Schlegelberger B, Himmler A, Bartles H, Kuse R, Sterry W, Grote W

Cancer Genet Cytogenet 1994 Nov;78(1):15-22

PMID 7987800

Diagnosis of small non-cleaved cell lymphoma by fine needle aspiration utilizing cytomorphologic features combined with cytogenetic analysis

Schmitz L, Beneke J, Kubic V

Acta Cytol 1997 May-Jun;41(3):759-64

PMID 9167698

Conventional cytogenetics of nodular lymphocyte-predominant Hodgkin's lymphoma

Stamatoullas A, Picquenot JM, Dumesnil C, Ruminy P, Penther D, Bertrand P, Courel MN, Maisonneuve C, François A, Gaulard P, Tilly H, Bastard C

Leukemia 2007 Sep;21(9):2064-7

PMID 17495968

Recurrent chromosomal abnormalities in lymphomas in fine needle aspirates of lymph node

Trcić RL, Sustercić D, Kuspilić M, Jelić-Puskarić B, Fabijanić I, Kardum-Skelin I

Coll Antropol 2010 Jun;34(2):387-93

PMID 20698107

Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group

Uckun FM, Sensel MG, Sather HN, Gaynon PS, Arthur DC, Lange BJ, Steinherz PG, Kraft P, Hutchinson R, Nachman JB, Reaman GH, Heerema NA

J Clin Oncol 1998 Feb;16(2):527-35

PMID 9469337

Citation

This paper should be referenced as such :

Zamecnikova A

der(21)t(1;21)(q11-12;p11-13) and der(21)t(1;21)(q21-32;p11-13);

Atlas Genet Cytogenet Oncol Haematol. in press

On line version : http://AtlasGeneticsOncology.org/Anomalies/t0121q11_32p11_13ID1478.html

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes

MECOM

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